The review’s central message is that the ER and Golgi are not merely passive way stations for proteins on their way to the cell surface. They are active hubs of metal ion homeostasis, carefully balancing the influx and efflux of Zn2+, Mn2+, and Fe2+ to meet the demands of the metalloenzymes resident in their lumens. Many of these enzymes simply cannot function without their metal partners. Glycosyltransferases in the Golgi, for example, often require manganese to catalyze the attachment of sugar chains onto proteins, a modification essential for proper protein function, trafficking, and recognition. Zinc, meanwhile, stabilizes protein structures and supports enzymes involved in folding and processing. Iron contributes to enzymes of the secretory pathway as well, although its handling in these organelles remains less well characterized than that of the other two metals. The precise mechanisms governing how each of these ions crosses the membranes of the ER and Golgi have only partially been resolved, and mapping them is one of the field’s central goals.

Over the past twenty years, several transporter families have emerged as key regulators of metal ion homeostasis in the secretory pathway. Among the most prominent are the Zrt/Irt-like proteins, known as ZIPs, which generally import zinc into the cytosol or organelles, and the zinc transporters of the ZnT family, which move zinc in the opposite direction. In the context of the ER and Golgi, specific members of these families have been pinpointed as critical suppliers of zinc to the lumen. The review highlights ZIP13 and ZIP11 in particular, both encoded within the SLC39A gene family, as secretory pathway zinc importers whose dysfunction has tangible consequences for the cell. On the export side, ZnT proteins of the SLC30A family help shape the zinc landscape of these compartments, ensuring that luminal concentrations remain within the narrow window that resident enzymes require.

Manganese transport tells a parallel but distinct story. The secretory pathway Ca2+/Mn2+ ATPase 1, or SPCA1, is a P-type ATPase embedded in Golgi membranes that pumps both calcium and manganese ions into the Golgi lumen at the expense of ATP. This pumping activity maintains the high luminal manganese concentrations needed by Golgi glycosyltransferases, which would otherwise be starved of their essential cofactor. Alongside SPCA1, the review discusses transmembrane protein 165, or TMEM165, another Golgi-resident protein implicated in manganese supply. Mutations in the genes encoding either protein are now recognized causes of congenital disorders of glycosylation, a class of rare inherited diseases in which defective sugar processing leads to multi-system developmental and physiological problems. The convergence of SPCA1 and TMEM165 on the same biochemical pathway underscores how vulnerable glycosylation is to disruptions in metal delivery.

What makes this review particularly timely is its synthesis of the disease connections that have accumulated over recent years. Dysregulation of ER and Golgi metal transporters is increasingly linked not only to congenital disorders of glycosylation but also to connective tissue disorders, neurodegenerative diseases, and cancer. ZIP13, for instance, has been implicated in a spondylocheirodysplastic form of Ehlers-Danlos syndrome, a connective tissue disorder in which defective zinc handling in the secretory pathway compromises the biosynthesis of extracellular matrix components. In the nervous system, altered metal homeostasis in the secretory pathway has been associated with neurodegenerative processes, reflecting the heavy metal demands of neurons and their extensive protein secretory machinery. In cancer, transporter expression patterns shift in ways that can support the altered metabolism and uncontrolled growth of tumor cells, making some of these transporters potential biomarkers or therapeutic targets.

One of the emerging concepts the authors emphasize is metal crosstalk within the secretory pathway. The ER and Golgi do not handle zinc, manganese, and iron in isolation from one another. Competition and cooperation among these ions, and among the transporters that move them, can reshape the metal composition of the entire pathway. When one metal is scarce or its transporter is compromised, the cell may compensate by redistributing others, sometimes with unintended consequences for metalloenzyme function. This interconnectedness means that studying a single transporter in isolation provides only a partial picture. The review argues that a systems-level understanding, one that considers how ZIPs, ZnTs, SPCA1, TMEM165, and iron-handling mechanisms interact, is needed to predict how cells respond to metal stress and how these responses fail in disease.

The technical challenges of studying metal transport in these organelles are considerable. Metal ions cannot be easily visualized in living cells without specialized fluorescent probes, and their concentrations in the ER and Golgi lumen are difficult to measure directly. Much of what is known has come from genetic studies in model organisms, cell biological experiments tracking transporter localization, and biochemical characterization of purified proteins. Each approach has limitations, and the review makes clear that significant gaps remain. For iron in particular, the transporters responsible for moving Fe2+ across ER and Golgi membranes are still not fully identified, and the review frames this as a key open question for the field to address in the coming years.

The authors also point toward future directions that could accelerate progress. Better probes for imaging labile metal ions in specific organelles would allow researchers to watch metal traffic in real time. Structural biology, including cryo-electron microscopy, is beginning to reveal the molecular architectures of transporters like SPCA1 and TMEM165, offering clues about how they discriminate between calcium and manganese or how disease mutations disable them. Genome editing technologies make it possible to model patient-specific transporter mutations in cell lines, creating platforms for testing corrective strategies. And because several of these transporters are membrane proteins accessible from the cytosolic side, they represent plausible drug targets, raising the prospect of pharmacological interventions that could restore metal balance in disorders of glycosylation or mitigate metal-related contributions to neurodegeneration and cancer.

For a field that began with the simple observation that Golgi enzymes need manganese, the scope of what has been learned is striking. The ER and Golgi now appear as sophisticated metal management centers, with dedicated importers, pumps, and regulatory mechanisms tuned to the needs of dozens of metalloenzymes. The review by Li, Zhang, Yang, and Zhou consolidates this knowledge into a coherent framework and, just as importantly, lays out the questions that remain. As the authors note, the precise mechanisms governing metal transport into and out of these organelles are still being elucidated, and the pathophysiological consequences of their disruption extend across an impressive range of human disease. What happens in these microscopic compartments, it turns out, resonates through the entire body, from the skeleton and connective tissue to the brain, and understanding the cell’s metal highway may ultimately open new avenues for treating disorders that have long resisted conventional approaches.

Subject of Research: Metal ion transport mechanisms and homeostasis in the endoplasmic reticulum and Golgi apparatus

Article Title: Metal ion transport in the ER/Golgi: zinc, manganese, and iron

Article References: Li, H., Zhang, Y., Yang, K., & Zhou, B. (2026). Metal ion transport in the ER/Golgi: zinc, manganese, and iron. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06487-5

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06487-5

Keywords: endoplasmic reticulum, Golgi apparatus, zinc transport, manganese, iron, ZIP transporters, ZnT transporters, SPCA1, TMEM165, glycosylation, metal ion homeostasis, metalloenzymes

The research, led by Shifat Ara Saiful and Ahmad H. Kabir of the University of Rajshahi and Lamar University together with colleagues in Bangladesh and the United States, focused on Rhizophagus irregularis, one of the most widespread arbuscular mycorrhizal fungi, or AMF. These fungi colonize the roots of most terrestrial plants and push out vast networks of hyphae into the surrounding soil, effectively extending the root system’s reach. Because hyphae can explore soil pores and access nutrient pools beyond the depletion zone that forms around roots, mycorrhizal plants can tap zinc reserves that non-colonized roots simply cannot reach. The fungi also release organic acids and chelating compounds that dissolve poorly available zinc, and they can regulate the expression of plant zinc transporters that move the metal from fungal structures into root cortical cells.

To test how much this symbiosis matters under zinc starvation, the team grew pea seedlings in carefully controlled hydroponic systems with either sufficient zinc, at 2.0 micromolar zinc sulfate, or deficient zinc, at 0.1 micromolar. Some plants received an inoculum of R. irregularis spores while others did not, producing four treatment groups. After five weeks, microscopic examination of trypan blue-stained roots confirmed that colonization occurred only in inoculated plants, which displayed the telltale fungal structures of mycelia, arbuscules, and vesicles. Molecular verification followed: PCR amplification of the fungus’s 18S rRNA gene produced clear bands in inoculated samples, and quantitative PCR showed significantly higher fungal abundance in colonized roots, regardless of whether zinc was plentiful or scarce.

The damage inflicted by zinc deficiency was unmistakable. Zinc-starved peas showed stunted shoots and roots, reduced dry weight of both organs, and lower turgid weight, a sign of impaired water status. Chlorophyll scores measured with a SPAD meter dropped, as did the photosynthetic performance index and the maximum quantum efficiency of photosystem II, both captured with chlorophyll fluorescence analysis. At the cellular level, the stress was equally evident: roots accumulated hydrogen peroxide, a reactive oxygen species, and leaked electrolytes, indicating membrane damage and disrupted redox balance. In short, zinc deficiency pushed the seedlings toward oxidative injury and photosynthetic collapse, a pattern consistent with zinc’s established roles in enzyme activation, protein synthesis, membrane integrity, and protection against reactive oxygen species.

Inoculation with R. irregularis dramatically reversed this decline. Colonized plants grown under zinc deficiency regained shoot height, root length, and biomass, and their chlorophyll scores and photosynthetic parameters rose to levels statistically comparable to healthier treatments. Hydrogen peroxide accumulation and electrolyte leakage fell significantly in the inoculated, zinc-starved plants, pointing to a protective effect on membranes and antioxidant systems. The best overall performers were plants that enjoyed both ample zinc and the fungal partner, but the crucial finding was that the fungus could largely compensate when zinc was limiting, restoring growth and physiology toward control levels.

Elemental analysis by inductively coupled plasma mass spectrometry revealed how the fungus reshaped mineral nutrition. Zinc concentrations in both roots and leaves fell sharply under deficiency, yet AMF inoculation restored tissue zinc levels significantly. The deficiency also disturbed the balance of other metals: iron and copper accumulated to excess in zinc-starved roots and leaves, likely through non-specific metal transporters and disrupted ion homeostasis, while manganese rose in roots. AMF colonization partially normalized iron and copper levels and further increased root manganese, suggesting the fungus fine-tunes the whole micronutrient network rather than simply delivering more zinc. Notably, other measured elements did not change across treatments, indicating that the mycorrhizal effect was element-specific.

At the molecular level, the fungus appeared to switch on the plant’s own zinc-import machinery. Quantitative real-time PCR showed that expression of the zinc transporter genes ZIP1 and ZIP2 increased in the roots of zinc-deficient plants, and that AMF inoculation pushed their expression even higher. ZIP-family transporters are central to zinc uptake and redistribution during micronutrient shortage, so their induction implies that the symbiosis works on two fronts: the fungal hyphae mobilize and deliver zinc from the soil, while the host simultaneously upgrades its internal transport pathways to receive and move the metal. This coordinated regulation helps explain how colonized plants achieved higher tissue zinc concentrations despite the severely limited supply in the growth medium.

The study also uncovered a striking metabolic dimension. Amino acid profiling of roots and leaves showed that zinc deficiency reprogrammed nitrogen metabolism extensively. Stress-associated amino acids such as histidine, lysine, threonine, valine, aspartic acid, glutamic acid, and proline accumulated, while growth-related amino acids including leucine, isoleucine, glycine, and tyrosine declined. This pattern reflects a classic stress response, shifting resources toward osmoprotection, nitrogen remobilization, and signaling at the expense of growth metabolism. AMF inoculation restored several of the depleted amino acids, particularly leucine, isoleucine, glycine, and tyrosine, in both roots and leaves. Because branched-chain amino acids support energy metabolism and stress recovery, and glycine and tyrosine feed antioxidative metabolism and secondary metabolite biosynthesis, their restoration suggests the fungus helps rebalance metabolism toward cellular repair and growth.

Perhaps the most compelling evidence came from a split-root experiment, in which the researchers divided each plant’s root system between two sealed compartments and applied different treatments to each side. When only one compartment was colonized by AMF while the other suffered zinc deficiency, the entire plant still benefited: shoot height, shoot dry weight, and chlorophyll scores improved even though half the root system never touched the fungus. In the treatment where both compartments received the fungus under sufficient zinc, plants matched the fully healthy controls. Compartment-specific effects did appear locally, with colonized roots showing greater elongation and lower hydrogen peroxide, but these localized changes were modest compared with the strong shoot-level recovery. The conclusion is that AMF trigger long-distance systemic signaling, likely involving phytohormones, reactive oxygen species, calcium, and nutrient-responsive pathways, that coordinates photosynthesis, biomass accumulation, and antioxidant defense across the whole plant.

The authors are careful to note the limits of their work. All experiments used pea seedlings in hydroponics, which allows precise control of zinc and fungal inoculation but cannot fully reproduce the complexity of soil-grown plants in the field. As a legume, pea also undergoes developmental shifts once rhizobial nodulation and nitrogen fixation begin, which could alter nutrient demand and root physiology in ways that seedling-stage data cannot capture. Future studies validating these responses across growth stages, in real soils, and in interaction with rhizobia are clearly needed. Even so, the findings carry real weight for sustainable agriculture. They show that a single mycorrhizal fungus can simultaneously improve zinc acquisition, restore metabolic balance, protect the photosynthetic apparatus, and broadcast resilience through systemic signals. As zinc deficiency constrains yields across vast tracts of micronutrient-poor farmland, AMF-based bioinoculants emerge as a promising, environmentally sound complement to fertilizers, one that works with the plant’s own biology rather than simply pouring more metal into the ground.

Subject of Research: Arbuscular mycorrhizal fungus-mediated systemic tolerance to zinc deficiency in pea plants

Article Title: AMF-mediated systemic regulation induces Zn-deficiency tolerance through nutrient and metabolic adjustment in pea plants

Article References: Saiful, S. A., Akter, M. N., Hasan, M. R., Reza, M. S., Mondal, T., Mim, F., Mostofa, M. G., Rahman, M. M., Karim, M. R., & Kabir, A. H. (2026). AMF-mediated systemic regulation induces Zn-deficiency tolerance through nutrient and metabolic adjustment in pea plants. Discover Plants, 3(1), Article 409. https://doi.org/10.1007/s44372-026-00886-5

Image Credits: AI Generated

DOI: 10.1007/s44372-026-00886-5

Keywords: arbuscular mycorrhizal fungi, Rhizophagus irregularis, zinc deficiency, pea, ZIP transporters, amino acid metabolism, systemic signaling, photosynthesis, oxidative stress, mineral homeostasis, biofertilizer, plant physiology